Dr. Robert B Jennings: Durham, USA
The International Academy of Cardiovascular Sciences is delighted to recognize his extraordi- nary achievements and honour Robert Jennings with its most prestigious Medal of Merit.
Dr. Robert B. Jennings graduated from the Northwestern University Medical School in Chicago Illinois in 1949 at the age of 22. After a rotating internship, he spent a year in research in the Pathology Department of the Medical School prior to entering the U. S. Navy in 1951 during the Korean War. He reported for duty at the Great Lakes Naval Hospital where he was assigned to the Pathology Service. After serving for two years as a Medical Officer, he transferred to the inactive reserve and became an Instructor in Pathology at Northwestern University. He spent much of the next 50 years studying the heart and pursuing a career in academic medicine.
His first job was a good one from the point of view of research. His only responsibility was to teach medical students general pathology for roughly six months of the year. The remainder of his time was available for research. He applied himself and was lucky in his choice of questions to study. He rose from instructor to professor in 10 years and became Chairman of the Department of Pathology in 1969 when he also was named Magerstadt Professor of Pathology.
The search for an answer to a single question has guided much of Dr. Jenning’s research on the heart, namely: What event or series of events kills myocytes when they are made acutely ischemic? In 1953, as well as now, necrosis is not obvious in the human heart for hours after a patient develops signs and symptoms of acute myocardial infarction. Jennings hypothesized that it was likely that cell death occurred much faster than the histological study of autopsy hearts indicated. Using experimental acute myocardial infarcts in which he knew the part of the heart that was going to die in sustained occlusion, he was able to show that myocytes tolerated 15 to 18 minutes of severe ischemia. He termed this “Reversible Injury”. However, longer periods of ischemia resulted in the death of more and more myocytes in the subendocardial myocardium. Although dead, these myocytes were grossly normal. This state was termed “Irreversible Injury”. The question then became one of ascertaining which changes occurred in the reversibly injured myocytes at the time of transition to irreversibility. Dr. Jennings was able to show, together with Charles Steenbergen and Charles Ganote that, at about the time of the transi- tion, electron microscopy indicated that the sarcolemma was disrupted. Functional assessment of sarcolemmal integrity in tissue slices prepared from irreversibly injured tissue confirmed this finding. Thus, loss of cell membrane integrity is considered to be the critical event that leads to the death of ischemic myocytes.
In a critical experiment performed in 1959 and 1960, Dr. Jennings attempted to learn precisely when myocytes passed the “point of no return”. He did this by reperfusing the ischemic myocytes with arterial blood after having exposed them to various periods of ischemia. Using this technique, he was able to show that myocytes remained revers- ibly injured for an extended period of time and moreover, that they did not die simultaneously. These findings served as the scientific basis of reperfusion therapy in man, a procedure developed in the mid-1970s by Rentrop and others.
In 1978, Dr. Jennings and his long time collaborator, Keith Reimer, gave a blueprint for the salvage of ischemic myocytes in the dog heart. They showed that there was a transmural wave front of cell death in acutely ischemic myocardium in which the subendocardial myocardium died first followed by the death of myocytes in the mid- and subepicardial myo- cardium. Cell death progressed transmurally as a function of collateral arterial flow until all myocytes destined to die were dead. Salvage was pos sible during the first six hours of ischemia but not thereafter. Thus, significant numbers of myocytes can be salvaged by reperfusion for an extended period of time. This work was done at the Duke University Medical Center where in 1975 Dr. Jennings became Chairman of Pathology and a James B. Duke Professor. These studies were the basis of the American Heart Association Discovery Health Channel Award in 2004 for a basic science discovery that led to a major advance in clinical medicine.
From 1978-90, a number of important studies looked at the mechanism of cell death. Most of these studies involved analysis of the changes occurring in reversibly and irreversibly injured myocytes during or as a consequence of reperfusion of the damaged tissue, demonstrating that massive sarcolemmal destruction occurs within seconds of the onset of reperfusion of irreversibly injured tissue, and that this change is associated with massive calcium loading. This was the first direct link between calcium loading and cell death. Anthony Shen and Dr. Jennings identified that the calcium came from the plasma reperfusing the tissue and that most of the calcium was actively accumulated by the mitochondria. Dr. Jennings also showed a close association between ATP depletion, lactate accumulation and cell death during the first episode of ischemia, and hypothesized that sarcolemmal disrup tion might be related to one or both of these changes, although ATP depletion and lactate accumulation slowed greatly during a second brief episode of ischemia. This unexpected observation led to the discovery of the phenomenon known as “Ischemic Preconditioning”. A bright graduate student named Charles Murry, who was working with Drs. Jennings and Reimer, showed clearly that a brief episode of reversible ischemia protected the heart against the effect of a prolonged episode of ischemia, and proposed that the slowed metabolic changes might be the cause of the beneficial effect. In any event, this was the strongest protective effect ever identified in the experimental animal heart and was shown to occur in the human heart as well.
In 1989, Dr. Jennings retired from the Chair in Pathology at Duke and continued to be active in research until 2003. He has been awarded multiple honors over the course of his career including the Borden award for the best research done while a medical student, a Markle Scholarship in Academic Medicine, the Peter Harris Award for Excellence in Research of the International Society of Heart Research in 1992, the Cardiovascular Pathologist of the Year Award by the American Society of Cardiovascular Pathology in 1993, and the American Heart Association’s Discovery Health Channel award in 2004.